Certain connective tissue diseases appear to be the consequence of cell mediated immune reactions. Our current investigations focus on the mechanisms by which lymphoid cells may regulate connective tissue metabolism in normal and pathological conditions associated with inflammatory reactions. Depletion of lymphoid cells in rheumatoid arthritis patients by continuous flow-cell separation (lymphophoresis results in clinical improvement in certain patients. Furthermore, in an experimental rat model, the appearance of arthritis appears to require recovery of lymphoid cell function following streptococcal cell wall induced immunosuppression, further defining a role for lymphoid cells in the etiology of this disease. In vitro, lymphocyte mediators stimulate fibroblast proliferation and collagen synthesis and also activate macrophages. Activation of macrophages influences connective tissue destruction through the production of collagenase and prostaglandins and can also modulate connective tissue formation through the production of monokines which stimulate fibroblast migration (chemotaxis), proliferation and collagen synthesis. These lymphocyte and macrophage products may provide the molecular link between the inflammatory response and the subsequent changes in connective tissue which accompany inflammation.